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Essential Medicines List (EML) 2019 Application for the inclusion of /, and / in the WHO Model List of Essential Medicines, as reserve second-line drugs for the treatment of multidrug-resistant (complementary lists of anti-tuberculosis drugs for use in adults and children)

General items

1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of the forthcoming WHO Model List of Essential Medicines (EML) and WHO Model List of Essential Medicines for Children (EMLc) to include the following medicines: 1) Imipenem/cilastatin (Imp-Cln) to the main list but NOT the children’s list (it is already mentioned on both lists as an option in section 6.2.1 Beta Lactam medicines) 2) Meropenem (Mpm) to both the main and the children’s lists (it is already on the list as treatment for in section 6.2.1 Beta Lactam medicines) 3) Clavulanic acid to both the main and the children’s lists (it is already listed as amoxicillin/clavulanic acid (Amx-Clv), the only commercially available preparation of clavulanic acid, in section 6.2.1 Beta Lactam medicines)

This application makes reference to amendments recommended in particular to section 6.2.4 Antituberculosis medicines in the latest editions of both the main EML (20th list) and the EMLc (6th list) released in 2017 (1),(2).

On the basis of the most recent Guideline Development Group advising WHO on the revision of its guidelines for the treatment of multidrug- or -resistant (MDR/RR-TB)(3), the applicant considers that the three agents concerned be viewed as essential medicines for these forms of TB in countries. In many low resource settings, patients with MDR/RR-TB and extensively drug-resistant (XDR- TB) are inadequately treated and this is often because medicines such as these are sparsely available to compose a suitable regimen(4). Imp-Cln and Mpm are collectively referred to as and have been classified among the Group C agents at the latest update of the WHO recommendations; their action is potentiated by the co-administration of Amx-Clv. Carbapenems have been shown to be effective in reducing treatment failure and death when used in MDR-TB treatment regimens. These agents should therefore become more widely available to specialized care centres of national TB programmes and other health care providers treating M/XDR-TB patients. As the numbers of TB cases decline in the world, the global market for anti-TB drugs shrinks; second‐line medicines used to treat M/XDR-TB are destined to become less easily available. Moreover, global stock outs occur regularly. The inclusion of Imp-Cln, Mpm and Amx-Clv on the EML is one more step to increase the confidence of pharmaceutical manufacturers to invest more in production of these medicines.

This request to the EML is very timely given the recent comprehensive update of WHO guidance, which attests to the importance of the three medicines in this application to strengthen treatment regimens in children and adults when other alternatives are compromised (see Table 1). It is expected to facilitate the combined efforts of national TB programmes, technical partners and funding agencies to improve the outcomes and reduce avoidable mortality for close to 600,000 new MDR/RR-TB patients estimated to develop active disease in the world each year.

Table 1. Grouping of medicines recommended for use in longer MDR-TB regimens, WHO, 2018

GROUPS MEDICINE Group A OR Lfx / Mfx Bdq Lzd Group B Cfz OR Cs / Trd Group C E Dlm Z Imipenem-cilastatin OR Meropenem1 Ipm-Cln / Mpm (OR ) Am / (S) OR Eto / Pto p-aminosalicylic acid PAS 1 Every dose of Imp-Cln and Mpm is administered with clavulanic acid, which is only available in formulations combined with amoxicillin (Amx-Clv). Amx-Clv is not counted as an additional effective TB agent and should not be used without Imp-Cln or Mpm.

2. Name of the focal point in WHO submitting or supporting the application (where relevant) The focal point is the Unit of Laboratories, Diagnostics and Drug-resistance of the Global TB Programme of WHO Headquarters (WHO/HTM/GTB/LDR). The technical personnel directly concerned are Dennis FALZON and Ernesto JARAMILLO.

3. Name of the organization(s) consulted and/or supporting the application The Global Drug Facility has been consulted.

4. International Nonproprietary Name (INN, generic name) of the medicine The WHO INN (generic name) of the medicines are Imipenem / cilastatin (5), meropenem (6), and amoxicillin and clavulanic acid (5). Technical sheets about each individual medicine are in Annex 1.

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Medicine Anatomical Common formulations Therapeutic Chemical (ATC) Imipenem / J01DH51 Powder for injection: cilastatin 250 mg (as monohydrate) + 250 mg (as sodium salt) in vial 500 mg (as monohydrate) + 500 mg (as sodium salt) in vial Meropenem J01DH02 Powder for injection: 500 mg (anhydrous) in vial 1 g (anhydrous) in vial Amoxicillin and J01CR02 Tablet: clavulanic acid 250 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) 500 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) 875 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) Powder for oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic acid/5 ml 250 mg amoxicillin + 62.5 mg clavulanic acid/5 ml

6. International availability – sources, of possible manufacturers and trade names Generic name Trade Names Availability Logistics Imipenem / Multiple, include: Primaxin, Widely available from Both medicines are intended for cilastatin Anipen, Cilapenem, Imenam, multiple manufacturers parenteral use. They are available as a Imiclast, Imipen, , Tienam powder for reconstitution and administered via a central intravenous line Meropenem Multiple, include: Merrem, Widely available from or port-a-cath. They must be given with Meronem, Meropen multiple manufacturers clavulanic acid in order to be effective in the treatment of MDR-TB Amoxicillin and Multiple, include: Augmentin, Widely available from Clavulanic acid is the active component, clavulanic acid Amoclan; Amoxi-Clav; multiple manufacturers but all available formulations are Apo-Amoxi-Clav; Clavulin; combined with amoxicillin. The Novo-Clavamoxin, Acarbixin preparation being recommended for Aclam, Addex, Ambilan inclusion is therefore Amx-Clv, that is given as along with every dose of Imp-Cln or Mpm. Amx-Clv is inexpensive, available as tablets or syrup, with no special storage or administration needs. The reconstituted suspension can be kept refrigerated for up to 7 days following which it should be discarded

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group The application for all three medications is for their inclusion as individual medicines without a square box symbol. These medications belong to the Beta-lactam class of , which includes several other agents that are not effective against MDR/RR-TB and XDR-TB. 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) It is estimated that 558,000 new MDR/RR-TB cases emerged in the world in 2017 and 230,000 patients died of this form of TB(4). Between 25,000 and 32,000 children are estimated to develop MDR-TB each year(7). Many of these cases go undetected and are not placed on appropriate treatment, increasing the risk that they die and continue to transmit drug-resistant strains to others in the community. In 2017, countries reported that about 139,000 patients started MDR-TB treatment worldwide. The effectiveness of these efforts varies considerably, and data reported for patient outcomes in recent years show that only about half the MDR/RR-TB patients complete their treatment successfully. Among patients with XDR-TB the likelihood of successful outcomes is even lower. Patients who are not cured - often because their treatment fails or is interrupted - risk persistent disease or death. Given these low levels of treatment success, all efforts must be made to ensure that effective medications to treat drug-resistant TB become more widely available to the patients who need them, particularly in low resource settings which carry the largest burden of MDR/RR-TB(4). The most recent data analysis conducted for the 2018 WHO MDR-TB treatment guidelines revision attests to the effectiveness of the carbapenems - Imp-Cln and Mpm - in patients in whom other agents cannot be used to compose an adequate regimen, such as those with strains resistant to fluoroquinolones or who develop drug intolerance (see GRADE summary of evidence tables in Annex 2 from (3)). The reason why the carbapenems place so low in the priority listing of choice in longer regimens is that they need to be administered parenterally (Table 1). The two carbapenems need to be given with Amx-Clv. The inclusion of all three agents in the forthcoming EML would promote their increased use by countries in such situations and can have a life-saving role.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills) The three medications have a particular role in the composition of longer treatment regimens for patients with MDR/RR-TB, particularly those who have additional resistance or intolerance to one or more of the agents in Groups A and B. A typical MDR-TB regimen starts with a combination of at least 4 TB medicine drugs considered to be effective, primarily from Groups A and B (Table 1). In such a case the regimen is strengthened by Group C agents. Both carbapenems in this application belong to Group C. Amx-Clv is given with each dose of the . Drug Treatment Regimen Duration of Special treatment diagnostics, see dosing by weight bands for adults and children treatment or in the updated 2018 WHO guidelines(8) monitoring facilities and skills Imipenem / >14y: 2 vials (1g+1g) IV twice daily Whole duration of IV administration; cilastatin longer MDR-TB monitoring for <15y: not used treatment adverse events (see sect 11) Meropenem >14y: 1 vial (1g) 3 times daily or 2 vials twice daily Whole duration of IV administration; longer MDR-TB monitoring for <15y: 20–40 mg/kg iv every 8 hours treatment adverse events (see sect 11) Amoxicillin and >14y: 125 mg 2 or 3 times daily, with each dose of carbapenem Whole duration of Monitoring for clavulanic acid <15y: 2-10 ml of suspension of 250 mg amoxicillin/62.5 mg longer MDR-TB adverse events clavulanic acid/5 ml, by weight band, with each dose of treatment (see sect 11) carbapenem 10. Summary of comparative effectiveness in a variety of clinical settings: tuberculosis (MTB) is resistant to most β-lactam antibiotics because it contains the gene blaC, which encodes an extended spectrum β lactamase (9). BlaC β lactamase is only transiently inhibited by most β lactamase inhibitors (i.e. and ) except for clavulanic acid, which irreversibly inhibits it(9),(10). The use of Amx-Clv against MTB has had mixed results. Of note, clavulanic acid is not available commercially without amoxicillin. An early bactericidal activity (EBA) study from South Africa showed no benefit of Amx-Clv over the control (11). A study from Pakistan examining the MIC of drug resistant clinical isolates of MTB found that 98% of the isolates were resistant to Amx-Clv (12). Another EBA study showed that over 7 days, Amx-Clv reduced the sputum colony- forming units (CFU) by an average of 0.1 log10 cfu/ml per day (in comparision, reduced CFU by 0.27 log10 cfu/ml per day) (13). However, the mild efficacy of Amx-Clv may not be shared by all the β lactam antibiotics. Mpm is hydrolyzed 5 times slower than Amx-Clv by blaC (9),(10) and there have been several studies evaluating its activity (combined with clavulanic acid) against MTB(14). In vitro studies have shown that the combination of clavulanate improves the MIC of Mpm from 8 to 1 μg/ml (15), that this combination sterilizes aerobic and anaerobic MTB cultures and was active against drug susceptible and XDR-TB strains (10). Results have been mixed with respect to the effect of Mpm+Clv on mouse mortality and on MTB CFUs in the lung and spleen(15),(16),(17),(18). The combination Imp-Cln+Clv also has activity against MTB, although in some studies Mpm+Clv seems to be superior(10). Human data are sparse (case-control studies, case reports) (16),(19), but Mpm+Clv as part of regimens (usually also containing linezolid) for patients with MDR-TB and XDR-TB has shown improved culture conversion and survival (20),(21),(22).

11. Summary of comparative evidence on safety1: Medicine1 Common or Significant Adverse Other Adverse Drug Paediatric Considerations Drug Reactions Reactions Imipenem / cilastatin , rash, GI upset, Uncommon: Not applicable oliguria/anuria, acute renal , Stevens- failure, anaemia, , Johnson syndrome, jaundice hepatitis, jaundice, hearing loss Meropenem Seizure, rash, hypoglycaemia, GI Uncommon: The safety and upset, anaemia agranulocytosis, Stevens- effectiveness have been Johnson syndrome, established for paediatric hepatitis, jaundice patients ≥3 months of age Amoxicillin and clavulanic acid Diarrhoea and abdominal Uncommon: No special considerations discomfort. and hypersensitivity and rash

1 see also package inserts for more information 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group The three agents are available for purchase from the GDF products list(23) Drug Price Comments (US$) Imipenem / cilastatin 500mg/500mg powder for injection: 31-36/ 10 vials - Meropenem 1g powder for injection: 3.7/vial - Amoxicillin and clavulanic acid 500 mg/125 mg tab: 10.21-13.28/100 tabs - 125 mg/31.25 mg oral suspension: 1.21/bottle (paediatric)

Regulatory information

13. Summary of regulatory status of the medicine (in various countries) The table below summarizes the regulatory status of the medications in this application vis-à-vis the US FDA and EMA. Drug Authority Regulatory status and indications (accessed 5 December 2018) Imipenem / US Food and Approval granted to Merck 26 November 1985. cilastatin Drug https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&Ap Administration plNo=050587 (FDA) Since then, multiple companies and formulations have been granted approval. European Reference number : EMEA/H/A-30/001187 Medicines EC Decision date: 10 March 2011 (on need to harmonise the prescribing information for Agency (EMA) Tienam in the European Union) https://www.ema.europa.eu/en/medicines/human/referrals/tienam Meropenem US Food and Approval granted to Pfizer on 21 June 1996. Drug https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&Ap Administration plNo=050706 (FDA) Since then, multiple companies and formulations have been granted approval. European Reference number : EMEA/H/A-30/1003 Medicines EC Decision date: 15 October 2009 (on need to harmonise the prescribing information for Agency (EMA) Meronem and associated names in the European Union) https://www.ema.europa.eu/en/medicines/human/referrals/meronem Amoxicillin and US Food and Approval granted to Neopharma 6 August 1984 for a formulation of Augmentin. clavulanic acid Drug https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&Ap Administration plNo=050564 (FDA) Since then, multiple companies and formulations have been granted approval.

European Reference number : CHMP/97898/2009 Medicines EC Decision date: 19 October 2009 (on need to harmonise the prescribing information for Agency (EMA) Augmentin in the European Union) https://www.ema.europa.eu/en/medicines/human/referrals/augmentin

The regulatory approval for these three medicines does not include TB among the indications. The WHO recommendation for their use in MDR-TB regimens is considered “off-label use” and justified by the severity of the disease and reduced options to treat this condition (best practices for “off-label use” of new medicines in MDR-TB regimens has been discussed extensively in a WHO report(17)).

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)

Drug Standard Reference (accessed 5 December 2018) Imipenem / United States http://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item= cilastatin Pharmacopeia 18983 (Imipenem Monohydrate (100 mg)) https://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item =18612 (Cilastatin Ammonium Salt (100 mg)) European https://crs.edqm.eu/db/4DCGI/View=I0090000 (Imipenem (70 mg)) Pharmacopeia https://crs.edqm.eu/db/4DCGI/View=C2170000 (Cilastatin sodium (10 mg)) Meropenem United States http://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item= Pharmacopeia 18135 (Meropenem (300 mg)) European https://crs.edqm.eu/db/4DCGI/View=Y0001252 (Meropenem trihydrate (110 mg)) Pharmacopeia Amoxicillin United States http://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item= and clavulanic Pharmacopeia 18409 (Amoxicillin (200 mg)) acid http://store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?sitex=10020:22372:US&item= 18624 (Clavulanate Lithium (200 mg)) European https://crs.edqm.eu/db/4DCGI/View=A0800000 (Amoxicillin trihydrate (200 mg)) Pharmacopeia https://crs.edqm.eu/db/4DCGI/View=L0720000 (Lithium clavulanate (125 mg))

15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary If this request is approved, it is proposed that modifications are made to the tabulations in section 6.2.4 Antituberculosis medicines of the lists as follows: - page 17 of the WHO Model List of Essential Medicines (20th list)(1) : Complementary List Reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (MDR‐TB) should be used in specialized centres adhering to WHO standards for TB control. Imipenem / cilastatin Powder for injection: 250 mg (as monohydrate) + 250 mg (as sodium salt) in vial 500 mg (as monohydrate) + 500 mg (as sodium salt) in vial Meropenem Powder for injection: 500 mg (anhydrous) in vial 1 g (anhydrous) in vial Amoxicillin and clavulanic acid Tablet: 500 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) Powder for oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic acid/5 ml 250 mg amoxicillin + 62.5 mg clavulanic acid/5 ml

th - page 15 of the WHO Model List of Essential Medicines for Children (6 list)(2) as follows:

Complementary List Reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (MDR‐TB) should be used in specialized centres adhering to WHO standards for TB control. Meropenem2 Powder for injection: 500 mg (anhydrous) in vial 1 g (anhydrous) in vial Amoxicillin and clavulanic acid Tablet: 250 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) 500 mg amoxicillin (as trihydrate) + 125 mg clavulanic acid (as potassium salt) Powder for oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic acid/5 ml 250 mg amoxicillin + 62.5 mg clavulanic acid/5 ml

2 Imipenem / cilastatin is not generally used to replace meropenem in children References 1. WHO Model List of Essential Medicines. 20th List [Internet]. Geneva, World Health Organization; 2017. Available from: http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017.pdf

2. WHO Model List of Essential Medicines for Children. 6th List [Internet]. Geneva, World Health Organization; 2017. Available from: http://www.who.int/medicines/publications/essentialmedicines/6th_EMLc2017.pdf

3. WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update (WHO/CDS/TB/2018.15) [Internet]. Geneva, World Health Organization. 2018. Available from: https://www.who.int/tb/publications/2018/WHO.2018.MDR-TB.Rx.Guidelines.prefinal.text.pdf

4. Global tuberculosis report 2018 (WHO/HTM/TB/2018.20) [Internet]. Geneva, World Health Organization; 2018. Available from: http://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf

5. WHO Drug Information. Recommended INN List 39. International Nonproprietary Names for Pharmaceutical Substances [Internet]. Geneva, World Health Organization. Vol. 12. 1998. Available from: http://apps.who.int/medicinedocs/index/assoc/s14167e/s14167e.pdf

6. International Nonproprietary Names for Pharmaceutical Substances (Rec. INN : List 29) [Internet]. Geneva, World Health Organization. Vol. 3. 1989. Available from: http://www.who.int/medicines/publications/druginformation/innlists/RL29.pdf

7. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis in children. Int J Tuberc Lung Dis. 2018 May 1;22(5):3–6.

8. WHO | WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update [Internet]. Geneva, World Health Organization. 2018 [cited 2018 Jul 30]. Available from: http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-mdr-rr-tb-treatment- 2018-update/en/

9. Hugonnet J-E, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis beta- lactamase by clavulanate. Biochemistry. 2007 Oct 30;46(43):11998–2004.

10. Hugonnet J-E, Tremblay LW, Boshoff HI, Barry CE, Blanchard JS. Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis. Science. 2009 Feb 27;323(5918):1215–8.

11. Donald PR, Sirgel FA, Venter A, Parkin DP, Van de Wal BW, Barendse A, et al. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis. Scand J Infect Dis. 2001;33(6):466–9.

12. Ahmed I, Jabeen K, Inayat R, Hasan R. Susceptibility Testing of Extensively Drug-Resistant and Pre-Extensively Drug-Resistant Mycobacterium tuberculosis against Levofloxacin, Linezolid, and Amoxicillin-Clavulanate. Antimicrob Agents Chemother. 2013 Jun;57(6):2522–5.

13. Chambers HF, Kocagöz T, Sipit T, Turner J, Hopewell PC. Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis Off Publ Infect Dis Soc Am. 1998 Apr;26(4):874–7.

14. Gonzalo X, Drobniewski F. Is there a place for β-lactams in the treatment of multidrug- resistant/extensively drug-resistant tuberculosis? Synergy between meropenem and amoxicillin/clavulanate. J Antimicrob Chemother. 2013 Feb;68(2):366–9. 15. Solapure S, Dinesh N, Shandil R, Ramachandran V, Sharma S, Bhattacharjee D, et al. In Vitro and In Vivo Efficacy of β-Lactams against Replicating and Slowly Growing/Nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2506–10.

16. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for Treatment of Tuberculosis in Mice and Humans. Antimicrob Agents Chemother. 2005 Jul 1;49(7):2816–21.

17. Veziris N, Truffot C, Mainardi J-L, Jarlier V. Activity of Carbapenems Combined with Clavulanate against Murine Tuberculosis▿ . Antimicrob Agents Chemother. 2011 Jun;55(6):2597–600.

18. England K, Boshoff HIM, Arora K, Weiner D, Dayao E, Schimel D, et al. Meropenem-clavulanic acid shows activity against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother. 2012 Jun;56(6):3384–7.

19. Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger EL, et al. World Health Organization Group 5 Drugs for the Treatment of Drug-Resistant Tuberculosis: Unclear Efficacy or Untapped Potential? J Infect Dis. 2013 May 1;207(9):1352–8.

20. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D’Ambrosio L, Tiberi S, et al. Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR- TB. Eur Respir J. 2013 Jun;41(6):1386–92.

21. Payen MC, De Wit S, Martin C, Sergysels R, Muylle I, Van Laethem Y, et al. Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis [Case study]. Int J Tuberc Lung Dis. 2012 Apr 1;16(4):558–60.

22. Dauby N, Muylle I, Mouchet F, Sergysels R, Payen M-C. Meropenem/Clavulanate and Linezolid Treatment for Extensively Drug-resistant Tuberculosis: Pediatr Infect Dis J. 2011 Sep;30(9):812–3.

23. Stop TB Partnership | Global Drug Facility (GDF) - GDF Product Catalogue [Internet]. [cited 2017 Jul 7]. Available from: http://www.stoptb.org/gdf/drugsupply/pc2.asp?CLevel=2&CParent=4

24. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (WHO/HTM/TB/2014.11) [Internet]. Geneva, World Health Organization; 2015. Available from: http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf

Annex 1. Drug information sheets (24)

Annex 2. GRADE tables (from online supplements to the (3))

a. 95% patients who received carbapenems also received at least one other newer drug (i.e. bedaquiline, linezolid or clofazimine). A sensitivity analysis excluding patients who received other newer drugs could not be performed. b. Randomization method unclear c. Risk differences and confidence interval from propensity score matched regression meta-analysis of individual patient records d. Small numbers e. Two out of four studies that reported adverse events for carbapenems only reported adverse events for selected drugs. f. Pooled incidence of adverse events of random effect in meta-analysis

a. Risk differences and confidence interval from propensity score matched regression meta-analysis of individual patient records b. Pooled incidence of adverse events from random effects meta-analysis